1. Field of the Disclosure
The present disclosure relates to novel 4-hydroxytamoxifen and endoxifen prodrugs and the synthesis of the same. Further, the present disclosure teaches the utilization of the novel 4-hydroxytamoxifen and endoxifen prodrugs in a treatment for breast cancer.
The treatment of breast cancer patients with the novel 4-hydroxytamoxifen and endoxifen prodrug compounds taught herein can particularly be beneficial in those patients presenting intrinsic (de novo) resistance to tamoxifen, due to deficient cytochrome P450 2D6 enzyme (CYP2D6) or drug interactions that inhibit the activity of CYP2D6. Further still, the present novel compounds are beneficial to treat ER positive breast cancer patients who can benefit from the use of lower doses of endocrine therapy for reduced side effects.
2. Description of Related Art
Tamoxifen has been the mainstay hormonal therapy for breast cancer that expresses the estrogen receptor (ER+) since the 1980s. Early descriptions of the tamoxifen compound can be found in U.S. Pat. Nos. 3,288,806 and 4,536,516, both of which are herein incorporated by reference in their entireties.
Nearly 70% of all diagnosed breast tumors are classified as ER+, most of which initially respond to tamoxifen treatment. (see ref. 1). However, approximately 8% of breast cancer patients present intrinsic resistance to tamoxifen (see ref. 2) mainly because these patients do not have a functional cytochrome P450 2D6 enzyme (CYP2D6), encoded by the polymorphic CYP2D6 gene, that is responsible for converting tamoxifen to its more potent metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen. (see ref. 3).
Indeed, breast cancer mortality was significantly increased in patients with CYP2D6 null-allele compared to wild type patients. (see ref. 4). Jordan and co-workers first reported that high first-pass metabolism of tamoxifen led to a significant increase in its activity and characterized the first active primary metabolite, 4-OHT (see refs. 5-6), which showed 30- to 100-fold greater potency than tamoxifen in inhibiting estrogen-dependent cell proliferation. (see ref. 7-9).
The predominant biotransformation route, demethylation of tamoxifen to form N-desmethyltamoxifen is catalyzed by the P450 enzyme CYP3A4/5. (see ref. 10). This major primary metabolite has potency similar to tamoxifen. It is then converted into the more potent secondary metabolite endoxifen exclusively by CYP2D6. On the other hand, the same CYP2D6 is required for the formation of 4-OHT, which is equally or more potent than endoxifen. While the hydroxylation at the 4C-position depends on CYP2D6, the biotransformation from 4-hydroxytamoxifen to endoxifen does not. In fact, it has been shown that CYP3A4/5 is primarily responsible for this metabolic route of 4-OHT demethylation leading to endoxifen formation. Thus, both endoxifen and 4-hydroxytamoxifen represent desirable alternatives to tamoxifen for breast cancer patients lacking the active form of the cytochrome P450 2D6 enzyme CYP2D6. (see refs. 11-15).
Despite this understanding, effective synthetic 4-OHT and endoxifen prodrugs remain unavailable, and there remains a need in the art for these compounds.